Faculty Collaboration Database

Radiation therapy results in preferential tumor antigen-specific lymphodepletion in head and neck cancer. Nat Commun 2025 Jul 01;16(1):5660

Date

07/02/2025

Pubmed ID

40593620

Pubmed Central ID

PMC12219838

DOI

10.1038/s41467-025-60827-w

Scopus ID

2-s2.0-105009625716 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (T^Prolif_Tox). We provide multi-dimensional evidence for tumor antigen-specificity of T^Prolif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC.

Author List

Zenga J, Awan MJ, Frei A, Foeckler J, Kuehn R, Kasprzak J, Massey B, Bruening J, Akakpo K, Shukla M, Wong SJ, Mathison AJ, Wendt Andrae J, Hunt B, Puzyrenko A, Jin VX, Memon AA, Villarreal Espinosa O, Chen F, Shaheduzzaman M, Kearl T, Hematti P, Himburg HA

Authors

Musaddiq J. Awan MD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin
Jennifer D. Bruening MD Assistant Professor in the Otolaryngology department at Medical College of Wisconsin
Peiman Hematti MD Professor in the Medicine department at Medical College of Wisconsin
Heather A. Himburg PhD Professor in the Radiation Oncology department at Medical College of Wisconsin
Bryan C. Hunt MD Associate Professor in the Pathology department at Medical College of Wisconsin
Victor X. Jin PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Tyce J. Kearl MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Becky Massey MD Associate Professor in the Otolaryngology department at Medical College of Wisconsin
Angela Mathison PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Monica E. Shukla MD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin
Stuart J. Wong MD Center Director, Professor in the Medicine department at Medical College of Wisconsin
Joseph Zenga MD Chief, Associate Professor in the Otolaryngology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Antigens, Neoplasm
Female
Head and Neck Neoplasms
Humans
Lymphocytes, Tumor-Infiltrating
Male
Middle Aged
Tumor Microenvironment